Project Summary: This application details a five-year career development program to facilitate the transition from a mentored post-doctoral fellow to an independent researcher. The applicant has completed 3.8 years of postdoctoral training at the University of California, Los Angeles. The applicant will continue to be mentored by Dr. Peter Tontonoz, a recognized leader in the field of lipid metabolism/signaling and associated disorders. Importantly, Dr. Tontonoz has overseen the career development of over 10 post-doctoral fellows now in independent academic positions, ensuring the quality of mentoring the applicant will receive under his tutelage. Continued interaction and collaboration with experts studying ApoE/A? metabolism in Alzheimer?s disease (Dr. Jungsu Kim, Mayo Clinic), and studying neuronal and synaptic plasticity (Dr.!Kelsey Martin, UCLA and Dr. Carlos Portera-Cailliau, UCLA), adds particular strengths to this application. Alzheimer?s disease (AD) is the most common cause of dementia in the elderly population. By far the strongest genetic risk factor for AD is apolipoprotein E (ApoE) genotype. In the brain, ApoE functions as a ligand for members of the lipoprotein receptor superfamily, including low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptors (VLDLR), and ApoE Receptor 2 (ApoER2). Brain ApoE receptors not only strongly impact the metabolism of both ApoE and A?, but also mediate signaling pathways required for maintaining synaptic plasticity and cognitive functions. Targeting brain ApoE receptors has recently emerged as a novel therapeutic strategy to combat AD. The applicant?s recent study and preliminary data showed a novel E3 ubiquitin ligase Idol is the major regulator of brain ApoE receptor expression, and has a profound impact on ApoE/A? metabolism and AD-like pathology. In this application, the Applicant proposes to further investigate the mechanisms through which Idol may impact the AD pathogenesis. The applicant will test the hypothesis that inhibiting the brain Idol pathway will not only increase A? clearance and reduce amyloid burden, but will also antagonize A?-induced synaptic dysfunction. Using transgenic AD mouse model (APP/PS1) with global, neuron-, or microglia-specific Idol deletion, the applicant will determine the effect of Idol deficiency on ApoE and A? metabolism in vivo, and evaluate the relative contributions from neurons and microglia (Aim 1). In addition, applicant will test the hypothesis that inhibition of neuronal Idol will prevent A?-induced synaptic dysfunction, and explore the underlying mechanisms (Aim 2). Finally, applicant will evaluate the impact of neuron- and microglia-specific Idol deletion to the neuropathological progression and cognitive function in APP/PS1 mice (Aim 3). Achievement of the aims in this proposal will not only further the scientific understanding of pathways modulating ApoE metabolism and signaling in the brain, but also provide validation of the potential utility of Idol as therapeutic target for AD pathogenesis.